- A new dietary ingredient (NDI) is defined as a dietary ingredient that was not marketed in the United States before October 15, 1994. Manufacturers and distributors must submit a notification to the FDA at least 75 days before marketing a dietary supplement containing an NDI. - The notification must include a description of the NDI, the manufacturing process, a safety narrative explaining why the supplement is reasonably expected to be safe, and a description of the supplement and its conditions of use. - Certain dietary ingredients that have been present in the food supply are exempt from the notification requirement if they have not been chemically altered. However, all dietary supplements containing an NDI, including exempt ones, must not cause the product

4. New Dietary Ingredient Definition of a Dietary Supplement: Contains an ingredient that could be used to supplement the diet Vitamin Mineral Herb, Amino acid, metabolite concentrate

5. New Dietary Ingredient Definition of a Dietary Supplement: Used for a human being Animal products are exempt from these requirements.

6. New Dietary Ingredient Three-Part Definition of a Dietary Supplement: Not presented as conventional food or for use as a sole item of a meal or of the diet. Tablet, Capsule, Powder, Softgel, Gelcap, Ex: packet of soup, stick of margarine, “potato chips”

7. New Dietary Ingredient Definition of a New Dietary Ingredient: A NDI is defined by statute as "a dietary ingredient that was not marketed in the United States before October 15, 1994.“ Is a NDI Notification required for a dietary supplement containing a NDI if the supplement contains only dietary ingredients that have been present in the food supply as articles used for food in a form in which the food has not been chemically altered? No.

8. New Dietary Ingredient Does the adulteration standard in 21 U.S.C. 342(f)(1)(B)[7] apply to a dietary supplement containing a NDI for which a NDI notification is not required because the supplement contains only dietary ingredients that have been present in the food supply as articles used for food in a form in which the food has not been chemically altered? Yes. The adulteration standard in 21 U.S.C. 342(f)(1)(B) applies to all dietary supplements that contain an NDI.

13. New Dietary Ingredient Is there an authoritative list of dietary ingredients that were marketed prior to October 15, 1994 (a so-called "grandfathered list" or "old dietary ingredient list")? No.

20. New Dietary Ingredient When should I submit separate NDI notifications for supplements that I manufacture or distribute containing the same NDI? It depends. If you have already submitted a NDI notification for a dietary supplement containing a NDI, you need not submit a notification for a different dietary supplement containing the same NDI as long as (1) the daily intake level recommended or suggested in the labeling of the new supplement will be equal to or less than that specified in your prior NDI notification, (2) the new supplement does not have other dietary ingredients that were not included in your original NDI notification, (3) the target populations (e.g., children or pregnant or lactating women) are the same or a subset of the target populations specified in your original notification, (4) all other conditions of use are the same as or more restrictive (e.g., fewer intended uses, shorter duration of use) than the conditions of use described in your prior NDI notification, and (5) FDA did not express safety or other concerns in response to your prior NDI notification.

21. New Dietary Ingredient Should I notify FDA about a microbial ingredient in my dietary supplement? Yes, if it is a NDI that has not been present in the food supply as an article used for food in a form in which the food has not been chemically altered (21 U.S.C. 350b(a)(1)). However, not all bacterial microorganisms are dietary ingredients, and a microorganism that is not a dietary ingredient cannot be a NDI.

22. New Dietary Ingredient Are food contact substances and other indirect food additives dietary ingredients? Not usually. Although food contact substances and other indirect food additives may be present in the food supply because they migrate into certain foods from packaging or other articles that contact the food, their presence in these foods is merely incidental. An indirect food additive is not a "dietary substance for use by man to supplement the diet by increasing the total dietary intake" (21 U.S.C. 321(ff)(1)(E)) because it is not consumed as a component of the diet, but merely as a byproduct of its use in articles that contact food.

23. New Dietary Ingredient If I alter the chemical structure of a dietary ingredient, is the new substance still a dietary ingredient? It depends. Altering the chemical structure of a dietary ingredient (e.g., creation of new stereoisomers, addition of new chemical groups as in esterification) creates a new substance that is different from the original dietary ingredient. The new substance is not considered to be a dietary ingredient merely because it has been altered from a substance that is a dietary ingredient and therefore is in some way related to the dietary ingredient; however, in rare instances, the new substance may independently qualify for one of the dietary ingredient categories listed in section 201(ff)(1) of the FD&C Act. For example, taurine is the end product of the metabolism of the amino acid cysteine. It is thus a metabolite of an amino acid and fits one of the definitions of a dietary ingredient (see 21 U.S.C. 321(ff)(1)(D), (F)). The enzymatic or synthetic processing of cysteine or any other dietary ingredient would be an appropriate method for the manufacture of a metabolite of a dietary ingredient like taurine for use in a dietary supplement.

24. New Dietary Ingredient Can an ingredient that has not been marketed as a food or as a dietary supplement, but has been approved as a new drug or licensed as a biologic, be used as a NDI in a dietary supplement? No, unless FDA issues a regulation, after notice and comment, finding that the ingredient, when used as or in a dietary supplement, would be lawful under the Act. A regulation of this type may be requested by filing a citizen petition under 21 CFR 10.30, but none has been issued to date. Absent such a regulation, an ingredient that has been approved as a new drug or licensed as a biologic can be a dietary ingredient for use in a dietary supplement if, and only if, prior to such approval or licensing, the ingredient was marketed as a dietary supplement or as a food.

25. New Dietary Ingredient Can I use an ingredient in a dietary supplement if it has been clinically tested as a drug but has not been approved as a drug in the U.S.? It depends on whether the ingredient was authorized for investigation in clinical trials under an investigational new drug application (IND), whether the date the IND went into effect was before or after the date the ingredient was first marketed as a food or as a dietary supplement, whether the clinical trials were "substantial clinical investigations," and whether their existence was made public. The general rule is that an article that has been authorized for investigation as a new drug or as a biologic before being marketed as a food or as a dietary supplement cannot be marketed as a dietary supplement if substantial clinical investigations of the article have begun and the existence of such investigations has been made public.

26. New Dietary Ingredient Who is required to submit a NDI notification? Either the manufacturer or distributor of a dietary supplement that contains a NDI, or the manufacturer or distributor of the NDI, must notify FDA at least 75 days before the dietary supplement containing the NDI is marketed in the U.S., unless the NDI has been present in the food supply as an article used for food in a form in which the food has not been chemically altered (21 U.S.C. 350b(a); 21 CFR 190.6(a)). Although FDA does review notifications from manufacturers or distributors of NDIs, notifications from ingredient manufacturers do not eliminate the requirement for a notification from the manufacturer or distributor of the dietary supplement in which the NDI will be used unless the prior notification for the NDI (1) included a description of the dietary supplement with the information required by 21 CFR 190.6(b), and (2) provided the history of use or other evidence of safety on the basis of which the notifier concluded that the dietary supplement would reasonably be expected to be safe under its labeled conditions of use.

27. New Dietary Ingredient What should be included in a NDI notification and how should it be presented? The required elements of a NDI notification are listed in 21 CFR 190.6(b).

28. New Dietary Ingredient How should the notification describe the NDI? Your notification should include (1) a statement that indicates what category of dietary ingredient, as defined in section 201(ff)(1)(A)-(F) of the FD&C Act, describes the NDI, and that explains the basis for this conclusion; (2) a description of the manufacturing process used to make the NDI, including process controls; (3) a description of the physical properties and chemical composition of the NDI; (4) a specification sheet that describes the critical safety attributes of the NDI, including the purity and strength of the NDI and the levels and identities of any impurities and contaminants.

31. New Dietary Ingredient When should a NDI notification be submitted? You must submit your NDI notification at least 75 days before you introduce or deliver for introduction into interstate commerce a dietary supplement that contains a NDI for which a notification is required (i.e., a NDI that has not been present in the food supply as an article used for food in a form in which the food has not been chemically altered) (21 U.S.C. 350b(a); 21 CFR 190.6 (a)).

32. New Dietary Ingredient How many copies of a NDI notification should be submitted? You should submit an original and one copy of the NDI notification.

42. New Dietary Ingredient What information should I submit if there is a history of use or other evidence of safety for a substance or product that is similar to, but not exactly the same as, my NDI or dietary supplement? You should use chemical, microbiological, and botanical characterizations, as appropriate, to explain how the substance or product is similar to your NDI or dietary supplement and to provide a rationale for how the safety information that is presented for the similar substance or product is relevant to the safety of your NDI or dietary supplement. Note that developing such a rationale requires knowledge of the identity (e.g., composition and strength) of the related substances that were studied or that have a history of safe use. The discussion in the notification should include the scientific rationale that supports extrapolating conclusions from a safety evaluation of the related substance or product to your NDI or dietary supplement. Otherwise, such evidence of safety may not provide a basis to conclude that your NDI or product will reasonably be expected to be safe.

44. New Dietary Ingredient How should the identity section of my NDI notification deal with toxins in related plants or microorganisms? You should identify the toxins or classes of toxins or other deleterious constituents or properties (e.g., antibiotic resistance genes in microorganisms or toxigenic properties for which the toxin is unidentified) known to be present in the same species or in a family or genus that is phylogenetically related to the NDI. You should also document the absence (or the amount, if present) of those toxins or other deleterious constituents or properties in the NDI, as well as in the substances that are the subject of the history of use or other evidence of safety presented in the notification.

48. New Dietary Ingredient What information should I provide if my notification includes an expiration date or "use by" date for the labeling of the NDI or the dietary supplement to which the NDI will be added? The expiration or "use by" date should be based on appropriate supporting stability data showing that (1) no new degradants will form during the labeled shelf life of the product under the conditions of storage specified in the notification, if any, or under normal storage conditions; and (2) the NDI or dietary supplement will continue to meet the critical safety attributes of identity, strength, and purity through its labeled expiration or "use by" date. You should provide these supporting data in the notification.

49. New Dietary Ingredient What information should I submit to describe the conditions of use that I intend to recommend or suggest in the labeling of my dietary supplement? Your notification must describe the conditions of use that will be recommended or suggested in the labeling of your dietary supplement or, if no conditions of use will be recommended or suggested in the supplement labeling, the ordinary conditions of use of the supplement (21 CFR 190.6 (b)(2)(ii)). Conditions of use include the dose (serving size), frequency of use (e.g., number of servings per day), duration of use, instructions for use, target population, and any restrictions on use, such as excluded populations. Daily lifetime use by all age groups at the highest recommended serving size will be assumed. Population restrictions could include exclusion of children, pregnant or lactating women, or sensitive individuals who should not consume the product. Allergen warnings are an example of a population restriction on conditions of use.

50. New Dietary Ingredient Should I submit both a history of safe use and safety testing data for the NDI? A notification should provide evidence of a history of safe use; other evidence of safety, including clinical and/or animal testing; or some combination of history of use and other evidence of safety. The submitted data should provide the basis for a conclusion that there is a reasonable expectation of safety under the proposed conditions of use of the dietary supplement containing the NDI. FDA expects that when history of use evidence alone is adequate to support the safety of the NDI in the supplement, notifiers will prefer to use that route. Compared to the cost and time needed to conduct clinical or animal toxicology studies, it is generally less expensive and faster to gather historical information and to conduct chemistry studies to establish the identity of the historically used materials. Submitting clinical and/or animal studies in addition to history of use data would be appropriate when the history of use evidence contains gaps or when the proposed conditions of use for the NDI differ from the historical conditions of use.

52. New Dietary Ingredient Where may I find information on how to estimate consumer intake? For references and information on methods of estimating consumer intake of food ingredients, including dietary ingredients in dietary supplements, refer to "Estimating Dietary Intake of Substances in Food“ and section III.G, "Intake Estimate," in "Recommendations for Submission of Chemical and Technological Data for Direct Food Additive Petitions." FDA is also aware of the existence of extensive analyses of consumption of specific conventional foods, especially in the U.S., in proprietary databases. Because these proprietary databases contain food categories much narrower than those described in public databases, they may be helpful in estimating consumer intake of a food constituent that becomes a NDI for use in a dietary supplement.

53. New Dietary Ingredient Are additional animal and human studies needed to support evidence of a history of safe use by humans? It depends on the situation. Data on history of use in humans should be the first evidence considered in evaluating the safety of a NDI. When the NDI has been previously consumed by humans, additional animal or human safety data are seldom needed if (1) the proposed use level is similar to or less than the levels safely consumed by humans in the past, and (2) the population expected to consume the NDI is the same as, or a subset of, the population that safely consumed the substance in the past.

55. New Dietary Ingredient What types of data would help in assessing safety if the dietary supplement containing the NDI is intended for daily chronic use, the NDI has a documented history of safe intermittent use, and the proposed use of the NDI leads to intake levels that are the same as or less than the levels consumed historically? (1) A three-study genetic toxicity (genetox) battery (bacterial mutagenesis, in vitro cytogenetics, and in vivo mammalian test) that includes a test for gene mutations in bacteria, either an in vitro mouse lymphoma thymidine kinase+/- gene mutation assay (preferred) or another suitable in vitro test with cytogenetic evaluation of chromosomal damage using mammalian cells, and an in vivo test for chromosomal damage using mammalian hematopoietic cells; (2) a 14-day range-finding oral study to establish a maximum tolerated dose (MTD) in an appropriate animal model; (3) a 90-day sub-chronic oral study in the same species as the range-finding study to establish an MTD and a No Observed Adverse Effect Level (NOAEL) for use in calculating the margin of safety; (4) a multi-generation rodent reproductive study (two generations); and (5) a teratology study (rodent or non-rodent).

56. New Dietary Ingredient What types of data would help in assessing safety if there is no history of use of the NDI that can be relied on to provide evidence of safe use in dietary supplements? (1) A three-study genetox battery as described in question 15; (2) 14-day range-finding oral studies to establish a maximum tolerated dose (MTD) in at least two appropriate species, at least one of which is non-rodent; (3) two 90-day sub-chronic oral studies (one for each species for which there is a range-finding study) to establish an MTD and a NOAEL for use in calculating the margin of safety; (4) a repeat-dose tolerability study in humans and/or an ADME study in animals and/or humans (30-90 day duration); (5) if proposed use is either intermittent or daily chronic, a one-year chronic toxicity study or a two-year carcinogenesis study in at least two animal species; (6) a multi-generation rodent reproductive study (two generations); and (7) a teratology study (rodent or non-rodent).

57. New Dietary Ingredient Where can I find FDA's current thinking about testing for food and color additives, and can I rely on this information when preparing my NDI notification? FDA's current thinking about testing for food and color additives is discussed in "Guidance for Industry and Other Stakeholders: Toxicological Principles for the Safety Assessment of Food Ingredients (Redbook 2000).“ This document provides general guidance on conducting standard toxicity tests. It also includes guidelines on conducting certain genetic toxicity tests, short-term toxicity tests, sub-chronic toxicity tests, one-year toxicity studies, and reproductive and developmental toxicity studies.

58. New Dietary Ingredient Am I required to use only FDA-published safety test protocols? No. Because there are no safety test protocols developed specifically for dietary ingredients, you should use your own judgment in selecting among FDA's protocols and other internationally recognized safety testing protocols and testing batteries developed for other types of products when you choose safety testing protocols for your NDI or the dietary supplement to which your NDI will be added. Regardless of the protocols used, you should cite the source for each protocol and why the protocol or the battery of protocols you chose is appropriate for the safety endpoints that are being investigated.

59. New Dietary Ingredient What is the appropriate duration for a sub-chronic oral toxicity study? Sub-chronic oral toxicity studies are generally conducted for at least 90 days (3 months). Protocols described as lasting 12 or 13 weeks are considered equivalent. The 90-day study provides information on the possible health hazards likely to arise from repeated exposure to a substance over a three-month period of time.

60. New Dietary Ingredient What kinds of human clinical studies are useful to support the safety of a NDI? The most useful studies are usually short-term tolerability studies and ADME studies. When human ADME studies are done in conjunction with ADME studies conducted in the animal species used for toxicological testing, the relevance of the animal data to humans can be demonstrated and the safety factors used to calculate the margin of safety can be reduced.

61. New Dietary Ingredient Where can I find more information and examples of clinical protocols that can be used in conducting human studies for NDIs and dietary supplements? For more information and sample clinical protocols, refer to Chapters V [45] and VI [46] of the Draft Redbook II, which provide general guidance on conducting human clinical studies on foods and food ingredients. FDA also recommends consulting "Guidance for Industry--M3 (R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" [47] for its discussion of selecting an appropriate dose for sub-chronic oral studies in animals and clinical trials in human volunteers (pp. 1-5).

62. New Dietary Ingredient What is the difference between a NOEL and a NOAEL, and which should I use? The No-Observed-Adverse-Effect Level (NOAEL) is a number signifying the highest dose or total daily intake level that did not elicit an adverse effect in a properly designed and executed toxicological study. [48] The No-Observable-Effect Level (NOEL) is the highest dose at which no effects are observed, including beneficial and neutral effects as well as adverse effects. Therefore, the NOAEL, which is the threshold for adverse effects, is the appropriate level to use in calculating the margin of safety for a NDI.

63. New Dietary Ingredient What safety information is required to support a NDI notification? You must provide the information that forms the basis on which you have concluded that a dietary supplement containing the NDI will reasonably be expected to be safe under the supplement's labeled conditions of use (21 U.S.C. 350b(a)(2)). In general, this information should include an adequate history of safe use, safety studies, or both.

65. New Dietary Ingredient What is an example of a common error about margin of safety in NDI notifications that have been submitted to FDA for review? Many manufacturers or distributors assume that if the NDI has a history of safe use in humans, no further safety discussion is warranted. That is incorrect. A margin of safety for NDI intake should be calculated, and the method of calculation explained and justified in the notification, even if a history of safe use is the basis of the safety evaluation.

66. New Dietary Ingredient What is an example of an example of a margin of safety calculation? The only safety evidence available is a single sub-chronic rat study during which no adverse effects were noted at the highest dose, which was the maximum tolerated dose of 3,000 mg/kg body weight. The top dose was limited by the fact that larger volumes could not be humanely administered to the animals. If the proposed conditions of use for the ingredient are 1 mg/person per day in adults daily, the EDI is (1 mg/person) /70 kg average adult = 0.014 mg/kg. The margin of safety is 3,000/0.014 = 2.1×105. The safety factors chosen are Ufintra × Ufextrap × Ufinter =10×10×20 = 2000. The ADI is 3,000/2,000 = 1.5 mg/kg. The EDI/ADI ratio is 0.014/1.5 = 0.01.This value is much less than one, which suggests that, if these safety factors are appropriate, the test article may reasonably be expected to be safe at the proposed daily intake level. An intake level of 1g per day (1000 times greater) would result in an EDI/ADI ratio of close to 10. More studies would be needed to justify the higher serving level.

68. New Dietary Ingredient Questions or Comments? James Lindon, Ph.D. Patent Attorney Lindon & Lindon, LLC 35104 Saddle Crk Cleveland (Avon), Ohio 44011-4907 Phone: 440-333-0011 Fax: 419-710-4925 [email_address] Patents, Trademarks, Copyrights, Pharmacy Law, Food and Drug Law For large files use http://dropbox.yousendit.com/JamesLindon939541 [this is not legal advice]